Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
  • A61K31/055—Phenols the aromatic ring being substituted by halogen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/075—Ethers or acetals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to methods of treating multiple sclerosis.
• the present invention relates to the protection of neurons and/or oligodendrocytes in multiple sclerosis patients with compounds of formula I, and structurally related compounds, as well as their isomers, racemates, enantiomers, their salts, and medicaments containing them.
• MS Multiple sclerosis
• Estrogen has been reported to protect oligodendrocytes from cytotoxicity induced cell death (Takao et al., 2004. J Neurochem. 89: 660-673) and 17 ⁇ -estradiol (E2) has been reported to hasten the elaboration of multiple, interconnecting processes on oligodendrocytes (Zhang et al., 2004. J Neurochem 89: 674-684).
• estrogen plays a direct protective role in response to degenerative disease and injury by enhancing cell survival, axonal sprouting, regenerative responses, synaptic transmission, and neurogenesis.
• CNS CNS
• estrogen-mediated cellular protection has been demonstrated in a number of in vitro models of neurodegeneration, including ⁇ -amyloid induced cytotoxic, excitotoxicity, and oxidative stress (Behl et al., 1995. Biochem. Biophys. Res. Commun. 216,473-482; Goodman et al., 1996.
• both natural estrogens and synthetic selective estrogen receptor modulators such as tamoxifen
• SERMs selective estrogen receptor modulators
• E2 or raloxifene protect neurons against l-methly-4-phenyl-l,2,3,6 tetrahydropyridine- induced toxicity (Callier, et al., 2001. Synapse 41: 131-138; Dhandapani and Brann, 2003. Endocrine 21: 59-66).
• Estrogen's neuroprotective effects are mediated through the modulation of bcl-2 expression, activation of cAMP and mitogen-activated kinase signaling pathways, modulation of intracellular calcium homeostasis, enhancement of antioxidant activity, and/or activation of estrogen receptors (ER) that can act as hormone-regulated transcription factors (Mangelsdorf, et al., 1995. Cell 83: 835-839; Katzenellenbogen, et al., 1996. MoI. Endocrinol. 10: 119-131; Singer et al., 1996. Neurosci. Lett. 212: 13-16; Singer et al., 1998. Neuroreport 9: 2565-2568; Singer et al., 1999.
• ERa and ER ⁇ Two characterized estrogen receptors, ERa and ER ⁇ , belong to the class I hormone receptor family that function as nuclear transcription factors.
• ERa and ER ⁇ (in the form of mRNA or protein) are expressed in neural cell types including Schwann cells, the myelin forming cells of the peripheral nervous system, and CNS neurons, astrocytes and oligodendrocytes (Miranda and Toran-Allerand, 1992; Santagati, et al., 1994; Kuiper, et al., 1996; Mosselman, et al., 1996; Thi et al. 1998; Platania, et al., 2003).
• oligodendrocytes the myelin forming cells of the CNS that are lost in MS, ERa has been reported to be nuclear, whereas ER ⁇ is cytolpasmic, in vivo immunoreactivity being readily detectable in cytoplasm and myelin sheaths (Zhang et al., 2004. J Neurochem 89: 674-684).
• Recently Arvanitis at al., 2004 J Neurosci Res. 75: 603-613 have reported an ER with similarities to ER ⁇ in isolated CNS myelin, the myelin sheath of spinal cord and brain sections and the oligodendrocyte plasma membrane.
• Mimicking and/or enhancing the beneficial effects of estrogen in MS by means of small molecules that are ligands at ER ⁇ , or compounds that preferentially mimic the effects of estrogen at sites other than the classical ERa is likely to have advantages for the treatment of MS in that the small molecules would be devoid of the untoward "hormonal" effects of estrogen which are mediated by ERa.
• These other ER sites may include the recently identified ER-X, which has been identified in neurons and is developmentally regulated (Toran-Allerand 2004. Endocrinology 145:1069-1074), or GPR30, which allows estrogen to trigger different pathways that integrate cell surface signaling with gene transcription (Kanda and Watanabe 2003. J Invest Derm 121: 771-780).
• These compounds may also be used to treat or prevent the development of other demyelinating diseases, including Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, Guillian-Barre syndrome, and disorders in which myelin-forming glial cells (oligodendrocytes or Schwann cells) are damaged, including spinal cord injury, neuropathies and nerve injury.
• demyelinating diseases including Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, encephalomyelitis, neuromyelitis optica, adrenoleukodystrophy, Guillian-Barre syndrome, and disorders in which myelin-forming glial cells (oligodendrocytes or Schwann cells) are damaged, including spinal cord injury, neuropathies and nerve injury.
• a subject of the invention is a new use for certain SERM-like phenylnaphthyl compounds that do not exhibit affinity for alpha or beta type estrogen receptors (ER) for the treatment of multiple sclerosis.
• ER estrogen receptors
• the compounds used in the treatment of the invention have the general formula (I):
• R 1 represents an alkyl radical containing from 1 to 4 carbon atoms or a hydrogen atom
• R 2 represents an alkyl radical containing from 1 to 4 carbon atoms or a hydrogen atom
• R 3 represents a hydrogen atom; a halogen atom; an alkyl radical containing from 1 to 4 carbon atoms; an -NR A R B group in which R A and RB are identical or different and represent a hydrogen atom, or an alkyl radical containing from 1 to 4 carbon atoms; NO 2 ; a 5- or 6- membered cyclic or heterocyclic radical; or an alkoxy radical containing from 1 to 4 carbon atoms
• R 4 represents a hydrogen atom; a halogen atom; a hydroxyl radical; an alkyl, alkenyl or alkynyl radical containing at most 4 carbon atoms; an alkoxy or alkylthio radical in which alkyl contains from 1 to 4 carbon atoms; or an -NR
• R 2 , R 3 , R 4 , R A and R B represent an alkyl radical containing from 1 to 4 carbon atoms, it is a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl radical.
• R 3 , and R 4 are a halogen atom, it is fluorine, chlorine, bromine or iodine. Preferably, it is chlorine.
• R 4 is an alkenyl radical containing at most 4 carbon atoms, preferably it is a vinyl or propenyl radical.
• R 4 is an alkynyl radical containing at most 4 carbon atoms, preferably it is an ethynyl or propynyl radical.
• R 3 or R 4 represent an alkyloxy radical containing from 1 to 4 carbon atoms, preferably it is a methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy radical.
• R 4 is an alkylthio radical containing from 1 to 4 carbon atoms, preferably it is a methylthio, ethylthio, propylthio, isopropylthio or butylthio radical.
• R 4 is an NR A R B radical in which R A and R B are identical or different and represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, preferably R 4 is an amino, methylamino, ethylamino, dimethylamino, diethylamino or methylethylamino radical.
• salts of the compounds of formula (I) in particular when the compounds of formula (I) contain an amino function.
• these are the salts formed, for example, with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, and alkanesulphonic acids such as methane- and ethanesulphonic acids, arenesulphonic acids, such as benzene and paratoluene sulphonic acids and arylcarboxylic acids.
• salts formed under the action of a base or an alkali or alkaline-earth metal in order to obtain, for example, derivatives such as sodium or potassium alcoholate or derivatives such as potassium or sodium phenolate.
• a preferred embodiment of the invention is the use of compounds such as those of formula (I) as defined above selected from the group consisting of:
• the compounds of formula I used in the process of this invention can be prepared by synthetic processes known in the art, for example, those disclosed in US Parent No. 6,147,119.
• “Pharmaceutically acceptable salts” means either an acid addition salt or a basic addition salt, whichever is possible to make with the compounds of the present invention.
• “Pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I.
• Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
• Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids.
• Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2- phenoxybenzoic, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
• Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated or substantially anhydrous form.
• the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which in comparison to their free base forms, generally demonstrate higher melting points.
• “Pharmaceutically acceptable basic addition salts” means non-toxic organic or inorganic basic addition salts of the compounds of Formula I. Examples are alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline. The selection of the appropriate salt may be important so that the ester is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
• Patient means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.
• Treating” or “treating” means any treatment, including, but not limited to, alleviating symptoms, eliminating the causation of the symptoms either on a temporary or permanent basis, or preventing or slowing the appearance of symptoms and progression of the named disorder or condition.
• “Therapeutically effective amount” means an amount of the compound,which is effective in treating the named disorder or condition.
• "Pharmaceutically acceptable carrier” is a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
• a pharmaceutical composition i.e., a dosage form capable of administration to the patient.
• pharmaceutically acceptable oil typically used for parenteral administration.
• “Stereoisomers” is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space.
• Formula (I) can be administered in any form or mode which makes the compound bioavailable in therapeutically effective amounts, including orally, sublingually, buccally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, topically, and the like.
• One skilled in the art of preparing formulations can determine the proper form and mode of administration depending upon the particular characteristics of the compound selected for the condition or disease to be treated, the stage of the disease, the condition of the patient and other relevant circumstances. For example, see Remington's Pharmaceutical Sciences, 18 th Edition, Mack Publishing Co. (1990), incorporated herein by reference.
• compositions of the present invention may be administered orally, for example, in the form of tablets, troches, capsules, elixirs, suspensions, solutions, syrups, wafers, chewing gums and the like and may contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate or orange flavoring.
• binders such as microcrystalline cellulose, gum tragacanth or gelatin
• excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like
• lubricants such as
• the dosage unit form When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.
• a liquid carrier such as polyethylene glycol or a fatty oil.
• Other dosage unit forms may contain other various materials, which modify the physical form of the dosage unit, for example, as coatings.
• tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
• a syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
• the compounds of Formula I of this invention may also be administered topically, and when done so, the carrier may suitably comprise a solution, ointment or gel base.
• the base for example, may comprise one or more of petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
• the solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
• the parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials.
• the dosage range at which compounds of Formula I exhibit their ability to act therapeutically can vary depending upon the particular compound, the severity of the condition, the patient, the formulation, other underlying disease states that the patient is suffering from, and other medications that may be concurrently administered to the patient.
• the compound of Formula I will exhibit their therapeutic activities at dosages of between about 0.001 mg/kg of patient body weight/day to about 100 mg/kg of patient body weight/day.
• SK-N-SH cells were plated at 50,000 cells/well in Costar Biocoat 96-well poly-D-lysine coated plates in EMEM (Minimum Essential Medium Eagle with Earle's salts) containing penicillin/streptomycin, L-glutamine, sodium pyruvate, non-essential amino acids and sodium bicarbonate. Cells were grown overnight in a 37° C incubator under 5% CO 2 . The next day, the medium was removed and replaced with fresh medium.
• EMEM Minimum Essential Medium Eagle with Earle's salts
• SK-N-SH cells were plated at 2X10 6 cells/well in 6-well polystyrene culture plates, in 2ml EMEM containing penicillin/streptomycin, L-glutamine, sodium pyruvate, non-essential amino acids and sodium bicarbonate. Cells were grown overnight at 37°C under 5% CO 2 .
• SK-N-MC Bcl-2 (neo) clone 218 was plated at 25,000 cells per well in Packard View plates in phenol Red free EMEM containing penicillin/streptomycin, L-glutamine, sodium pyruvate, non-essential amino acids, sodium bicarbonate and 200ug/ml G418. Cells were grown overnight in a 37°C incubator under 5% CO2.
• OLIGODENDROCYTE toxicity assay Primary rat oligodendrocyte progenitor cells were obtained from the cerebra of 2-3 day old postnatal rats (Sprague Dawley). The meninges were removed and tissue was mechanically dissociated. Cells were plated on T75 flasks and fed with DMEM + 10% FBS.
• Enriched OLPs were collected by mechanical separation from the astrocytic monolayer and were expanded in serum free media (SFM) supplemented with the mitogens, PDGF-AA (lOng/ml) and FGF-2 (lOng/ml).
• SFM serum free media
• progenitor cells were switched to SFM supplemented with IGF-I (10ng/ml) 24 hours after plating and cells were grown under these conditions for 7 days prior to experimental assays.
• the target cells assessed in vitro are: human neuroblastoma cell lines [SK-N-SH, SH-S Y5 Y], and primary cultures of rodent oligodendrocyte progenitors and their mature counterparts.

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